Gastrointestinal inflammation is one of the most common types of inflammatory process which affects humans. Inflammatory bowel disease (IBD), a form of chronic gastrointestinal inflammation, includes a group of chronic inflammatory disorders of generally unknown etiology, e.g., ulcerative colitis (UC) and Crohn's disease (CD). Clinical and experimental evidence suggest that the pathogenesis of IBD is multifactorial involving susceptibility genes and environmental factors. The interaction of these factors with the immune system leads to intestinal inflammation and dysregulated mucosal immunity against commensal bacteria, various microbial products (e.g., LPS) or antigens (Mayer et al. Current concept of IBD: Etiology and pathogenesis. In “Inflammatory Bowel Disease” 5th edition 2000, Kirsner J B editor. W. B. Sanunders Company, pp 280-296).
Animal models of colitis have highlighted the prominent role of CD4+ T cells in the regulation of intestinal inflammation. Cytokine imbalance and the production of inflammatory mediators have been postulated to play an important role in the pathogenesis of both experimental colitis and IBD. Animal models of colitis include the dinitrobenzene sulphonic acid-induced colitis (DNB) model (Neurath et al. (2000) Int Rev Immunol 19:51-6), which mimics CD; and the dextran sodium sulphate (DSS) model, where DSS induces acute and chronic colitis (Dieleman et al. (1998) Clin Exp Immunol 114:385-91). Studies using transgenic mice having deletions in a cytokine gene develop a spontaneous inflammatory bowel disease (for a review see, e.g., MacDonald (1997) Eur J Gastroenterol Hepatol 9(11):1051-50). The inflammatory process and the immune response at mucosal sites result in mucosal barrier dysfumction leading to further exposure to enteric bacteria and/or their products that perpetuate mucosal inflammation.
Immunosuppressive and anti-inflammatory agents in high maintenance doses are the principal drugs used in the therapy of chronic inflammatory gastrointestinal disorders. Anti-inflammatory drugs presently used in treatment of IBD include aminosalycilates and immunosuppressive agents such as corticosteroids, azathioprine, cyclosporine and methotrexate. Corticosteroids remain the mainstay of anti-inflammatory and immunosuppressive therapy for many gastrointestinal conditions. Specific anti-TNF antibodies have also been used for treatment of IBD. About 20-25% of the patients with UC fail to respond to intensive and optimal medical therapy and therefore are referred to surgery for total proctocolectomy. In general, patients with CD are less responsive to medical therapy and usually do not respond to surgical treatment. Anti-TNFα antibodies have also been introduced to treat patients with CD with some efficacy, but this approach is ineffective in patients with UC. Thus, IBD is a medical problem that lacks an effective treatment.
Management of gastrointestinal inflammation, particular chronic gastrointestinal inflammation, is important, since the presence of gastrointestinal inflammation can be an early sign for risk of development of further serious conditions. For example, colorectal cancer represents the major cause for excess morbidity and mortality by malignant disease in ulcerative colitis as well as in Crohn's disease. The risk for ulcerative colitis associated colorectal cancer is increased at least 2-fold compared to the normal population. Colorectal cancer is observed in 5.5-13.5% of all patients with ulcerative colitis and 0.4-0.8% of patients with Crohn's disease. Ulcerative colitis associated colorectal cancer typically can occur in the entire colon, is often multifocal and of undifferentiated histology. Stage distribution and prognosis of ulcerative colitis associated colorectal cancer appears to be similar to that of sporadic colorectal cancer with an overall survival of about 40% (15-65%) after 5 years with tumor stage at diagnosis being the most important predictive parameter for survival (for a review see, e.g., Pohl et al. (2000) Hepatogastroenterology 47(31):57-70). Restorative proctocolectomy with a pouch made in the distal ileum is a common surgical procedure used in the treatment of ulcerative colitis; however, such can result in pouchitis. Pouchitis is an inflammation of the pouch created as treatment of a patient with ulcerative colitis (see, e.g., Sandbom et al. (1999) Inflammatory Bowel Diseases 5:33-39). Gastrointestinal symptoms of pouchitis include incontinence, bleeding, fever, and urgency.
There is a need in the art for effective methods of treating gastrointestinal inflammation, particularly chronic gastrointestinal inflammation such as IBD. The present invention addresses this need.
Literature
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